Abstract：
:Proprotein convertases (PCs) represent highly selective serine proteases that activate their substrates upon proteolytic cleavage. Their inhibition is a promising strategy for the treatment of several pathologies including cancer, atherosclerosis, hypercholesterolaemia, and infectious diseases. Here, we present the first experimental complex of furin with a non-substrate-like small molecule inhibitor, and the X-ray structure of the enzyme complexed to the small molecule inhibitor 1 at 1.9 Å resolution. Two molecules of inhibitor 1 were found to interact with furin. One is anchored at the S4 pocket of the enzyme and interferes directly with the conformation and function of the catalytic triade; the other molecule shows weaker binding and interacts with a distant, less conserved region of furin. The observed binding modes represent a new inhibition strategy of furin and imply the possibility to attain specificity among the PCs providing an innovative starting point of structure guided inhibitor development for furin.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Dahms SO,Jiao GS,Than MEdoi
10.1021/acschembio.6b01110subject
Has Abstractpub_date
2017-05-19 00:00:00pages
1211-1216issue
5eissn
1554-8929issn
1554-8937journal_volume
12pub_type
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